TRPV6 and Cav1.3 Mediate Distal Small Intestine Calcium Absorption Before Weaning

Abstract

Maintaining a positive calcium balance is vital for bone mineralization during postnatal development. We delineate transcellular calcium absorption pathways in the jejunum and ileum, which are present only early in life and contribute to a positive calcium balance. BACKGROUND & AIMS: Intestinal Ca 2þ absorption early in life is vital to achieving optimal bone mineralization. The molecular details of intestinal Ca 2þ absorption have been defined in adults after peak bone mass is obtained, but they are largely unexplored during development. We sought to delineate the molecular details of transcellular Ca 2þ absorption during this critical period. METHODS: Expression of small intestinal and renal calcium transport genes was assessed by using quantitative polymerase chain reaction. Net calcium flux across small intestinal segments was measured in Ussing chambers, including after pharmacologic inhibition or genetic manipulation of TRPV6 or Ca v 1.3 calcium channels. Femurs were analyzed by using micro-computed tomography and histology. RESULTS: Net TRPV6-mediated Ca 2þ flux across the duodenum was absent in pre-weaned (P14) mice but present after weaning. In contrast, we found significant transcellular Ca 2þ absorption in the jejunum at 2 weeks but not 2 months of age. Net jejunal Ca 2þ absorption observed at P14 was not present in either Trpv6 mutant (D541A) mice or Ca v 1.3 knockout mice. We observed significant nifedipine-sensitive transcellular absorption across the ileum at P14 but not 2 months. Ca v 1.3 knockout pups exhibited delayed bone mineral accrual, compensatory nifedipine-insensitive Ca 2þ absorption in the ileum, and increased expression of renal Ca 2þ reabsorption mediators at P14. Moreover, weaning pups at 2 weeks reduced jejunal and ileal Ca v 1.3 expression. CONCLUSIONS: We have detailed novel pathways contributing to transcellular Ca 2þ transport across the distal small intestine of mice during development, highlighting the complexity of the multiple mechanisms involved in achieving a positive Ca 2þ balance early in life.

TRPV Subfamily (TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) Gene and Protein Expression in Patients with Ulcerative Colitis

“…The functional roles of TRPV5 and TRPV6 are interconnected with each other, given that TRPV5 knockout mice upregulate their intestinal TRPV6 expression to compensate for the negative Ca 2+ balance caused by the loss of TRPV5mediated Ca 2+ reabsorption in the kidney [15][16][17]. Changes in the expression of TRPV5 and TRPV6 could be involved in the development of IBD and bone-related extraintestinal manifestations [18].…”

Structure and function of the calcium‐selective TRP channel TRPV6

“…While TRPV5, which expression is mainly restricted to the kidney, is considered the major epithelial calcium channel for renal Ca 2+ reabsorption, TRPV6 is considered the principal epithelial calcium channel for Ca 2+ absorption in intestines and many other organs. Interestingly, in mice, TRPM7, rather than TRPV6, has been recently proposed to play the major role in intestinal Ca 2+ absorption (Mittermeier et al, 2019), although in early development, TRPV6 contribution might still be critical (Beggs et al, 2019;Lee et al, 2019). In this review, we will focus on TRPV6.…”

“…2019), although in early development, TRPV6 contribution might still be critical (Beggs et al . 2019; Lee et al . 2019).…”

Dynamics of Intestinal Calcium Absorption in Neonates

“…Until recently, little was known on the mechanisms of Ca 2+ absorption in the developing neonate. A study presented by Beggs et al 5 in the current issue of Cellular and Molecular Gastroenterology and Hepatology thoroughly investigated the developmental changes in the functional expression of Ca 2+ transporters among the small intestine in mice. The expression of calbindin-D 9k appeared after weaning in the duodenum, whereas the jejunum and ileum demonstrated a reciprocal pattern, indicating a dynamic change in the transcellular Ca 2+ absorption site.…”

“…While molecular techniques such as in situ hybridization and immunohistochemistry have aided in the identification of nutrient transporters and their segmental heterogeneity, the Alexander group3, 5 has employed the Ussing chamber system (ex vivo). This classic electrophysiological assay is suited to quantifying transporter functions, especially in the transcellular pathway under voltage-clamping (short-circuit) conditions and is able to simultaneously compare diverse regions.…”